Natural products provide a wide range of biologically active agents, many of which have unique profiles of pharmacological activity and therapeutic potential. Over three hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins, which are noncompetitive blockers of nicotinic receptor channel complexes and potassium channels, pumiliotoxins, which are noncompetitive blockers of nicotinic receptor channel complexes and potassium channels, pumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, an extremely potent and selective nicotinic agonist with remarkable antinociceptive activity. Further alkaloids include 2,5-disubstituted decahydroquinolines, 3,5- disubstituted pyrrolizidines, 3,5-disubstituted indolizidines, 5,8- disubstituted indolizidines, 1,4-disubstituted and 4,6-disubstituted quinolizidines, the pumiliotoxin-homopumiliotoxin-allopumiliotoxin class, and a variety of tricyclic alkaloids, including pyrrolizidine oximes, pseudophrynamines, cyclopentaquinolizidines and coccinellines. Most of these alkaloids have been detected and characterized from neotropical dendrobatid frogs. Pumiliotoxins also occur in one genius of Australian myobatrachid frogs, in one genus of South American bufonid toads and in one genus of Madagascan mantellid frogs. The myobatrachid frogs also contain a unique class of physostigmine-like alkaloids, the pseudophrynamines, while the bufonid toads and the mantellid frogs contain, in addition to pumiliotoxins, a wide array of pyrrolizidines indolizidines, quinolizidines, decahydroquinolines and tricyclic alkaloids. Batrachotoxins occur in a New Guinea bird and alkaloids have been detected in two other birds. Structures of a number of further alkaloids are currently under investigation. Pyrrolizidine oximes have been shown to be nicotinic blockers and pseudophrynamine to be a sodium channel blocker. The antinociceptive activity of epibatidine has been further defined and proposed to be due to agonist activity at alpha3beta4 and alpha4beta2 nicotinic receptors. Calcium channel activity is involved in the antinociceptive effects of epibatidine. Analogs of epibatidine are being synthesized. It appear all frog skin alkaloids have a dietary origin, being taken up a sequestered unchanged into skin glands. Ants, beetles and millipedes appear to be the source of certain frog skin alkaloids. The origin of the batrachotoxins, histrionicotoxins, pumiliotoxins, decahydroquinolines and epibatidines found in frog skin remains a mystery.